Sharing some potentially significant findings relating to Omicron given the current situation. First of all huge thanks to the team working flat out- Bo Meng, @isabella_atmf and to our collaborators both in G2P, J2P along with @SystemsVirology. Findings as follows:
1. Omicron Spike protein mediates deficient cell entry and is inefficiently cleaved compared to Delta spike. We tested viral entry mediated by Wild Type, Delta and Omicron spikes using a pseudotyped virus system, infecting primary 3D lung alveolar organoids. Image
2. Omicron Spike protein induces relatively poor cell-cell fusion compared to WT and Delta. We expressed spike in cells stably expressing split GFP, so that Green signal could be measured over time upon cell-cell fusion and syncitia formation. The difference is significant. Image
3. What does this all mean? Efficient infection of lung cells could correlate with severity of lung disease. Syncitia or fused cells are often seen in respiratory tissues taken following severe disease. Delta was very good at both, in contrast to Omicron. Further work is needed
4. We also tested how well antibodies from vaccinated individuals neutralised Omicron v Delta. We found that Omicron was poorly neutralised after two doses of mRNA or Ad vectored vaccine compared to Delta, but that the third dose (mRNA vaccine) rescued this at an early time point Image
5. In summary this work suggests that Omicron does appear to have become more immune evasive, but that properties associated with disease progression *may* be attenuated to some extent. The significant growth of Omicron nevertheless represents a major public health challenge.
some more collaborator acknowledgements @JooHyeonLeeLab @Adamsizler Leo James and Guido Papa @MRC_LMB , Paul Lehner lab, and @Sci_Lipi

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More from @GuptaR_lab

May 4
COVID-19 vaccine elicited immune responses in Africa are understudied. We teamed up with The Nigerian Institute for Medical Research (NIMR) to examine AZ vaccine responses in the context of background prior infections and breakthrough infections. citiid.cam.ac.uk/wp-content/upl…
We first measured baseline SARS-CoV-2 seroprevalence prior to vaccination using flow cytometry methods for binding antibodies to nucleocapsid (N), coupled with virus neutralisation approaches for protective neutralizing antibody responses to VOC (January 2021)
In 140 participants, we found a high level - 62/140 (44%) of participants were previously infected with SARS-CoV-2 as evidenced by presence of Nucleocapsid (N) antibodies in early 2021 (N is absent from vaccines used in Nigeria, therefore presence indicates a past infection).
Read 14 tweets
Apr 29
Our paper on HIV-1 intrahost evolution under antiviral therapy out after >5 years in the making. @steveo_kemp R Goldstein, A Derache, @Tuliodna D Martin @CollinsIwuji ANRS TasP. Major implications for SARS-CoV-2 and resistance to therapeutics : journals.asm.org/doi/full/10.11…
Here we wanted to study HIV-1 evolution within individuals who were unable to suppress the virus with antiretroviral therapies. This was mainly due to sub optimal adherence to treatment, as drug levels in blood were measured and often low. Main findings:
1. Over periods of a year or more we observed significant changes in viral populations, with large fluctuations in synonymous and nonsynonymous variant frequencies despite stable viremia. Image
Read 7 tweets
Feb 2
Quick explainer on some of the key findings in our recent paper. nature.com/articles/s4158…. We find Omicron spike binds ACE2 better than Delta. Both variants replicate similarly in nasal cell cultures, but in airway cells high in TMPRSS2 there was significant impairment for Omicron
Spike cleavage by furin proteases during virus production in cells allows spike to use TMPRSS2, a cell membrane protease. Omicron (grey) is impaired in cell entry relative to Delta (orange) and Wu-1 (black) when TMPRSS2 (T2) overexpressed; ACE2 (A2) levels impact effect size (R)
We found that consistent with impaired use of TMPRSS2, the Omicron spike was inefficiently cleaved (as shown by the ratio of S2:full length spike). This came as a surprise because Omicron has three mutations around the polybasic cleavage site.
Read 10 tweets
Dec 23, 2021
Preprint on Omicron updated with further findings. Firstly, we see that the spike has altered its preference for the receptors it uses. SARS CoV-2 entry into a cell can occur via two routes: one that only needs ACE2 and another that needs ACE2 and TMPRSS2. biorxiv.org/content/10.110…
TMPRSS2 (T2) is higher in the lower airways and so virus goes the second route in those areas. Omicron spike has reduced ability to use the ACE2+T2 route and doesn't respond to higher T2 levels, unlike Delta in the figure. Also, Omicron entry is not blocked by drugs against T2.
We looked at therapeutics against live Omicron virus versus Delta and find that the REGN2 cocktail (Ronapreve) has almost no in vitro activity against Omicron, though activity of Molnupiravir and Remdesivir are preserved, as shown by other studies.
Read 4 tweets
Jul 17, 2021
Sharing our updated pre-print on Delta Variant and emergence, replication and immune evasion properties. We previously reported partial evasion of neutralising antibody responses following vaccination and breakthrough in vaccinated health care workers. biorxiv.org/content/10.110…
We now further define Delta immune evasion using a panel of 38 monoclonal antibodies, showing significant loss of potency of NTD and RBD targeting antibodies. Imdevimab, part of the REGN2 dual monoclonal antibody cocktail is compromised by Delta.
We also show loss of activity for casivirimab, part of the Lily dual therapy cocktail. These dual therapies could be less effective against Delta particularly in the setting of immune compromise could lead to escape variants emerging/ transmitting.
Read 6 tweets
Jun 24, 2021
Sharing our Delta work with @AnuragAgrawalMD @flaxter @DrSamirBhatt @wendybarclay11 @CambridgeBRC @Gui_Pap , INSACCOG, Leo James lab LMB, proposing Delta’s explosive emergence in India lies in increased transmissibility combined with immune evasion. researchsquare.com/article/rs-637…
Is Delta 25% more transmissible😑? 50%😳? 100%😱? Read on for the answer...But first: we argue that transmission is only half the story! Breakthrough infections and our lab studies point towards significant immune evasion, something seen with Beta and Gamma (but not Alpha).
In India’s second wave, mathematical modelling suggests that Delta reinfected many who had been infected in the first wave. How do we know? @creswapi, @MellanTom, @charliewhittak fit a 2-category Bayesian disease transmission model to genomic surveillance, serology, and deaths.
Read 13 tweets

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